Reviews & Analysis

MYC is a transcription factor controlling growth and nutrient metabolism. Luo et al. now link intestinal expression of MYC to impairments in glucose, lipid and body-weight homeostasis by uncovering novel roles of MYC in regulating the glucagon-like peptide GLP1 and the ceramide-biosynthesis regulator CERS4. Myc deletion in the intestinal epithelium prevents or reverses diet-induced obesity and hepatic steatosis in mice. Critically, people with obesity display elevated MYC and CERS4 expression in the ileum, thus further supporting the clinical relevance of these findings.

The molecular pathophysiology of diabetes in pancreatic islets remains largely a poorly understood ‘black box’ because of the inaccessibility of pancreatic tissue from living humans for molecular analysis. Wigger et al. now explore the transcriptional and proteomic profiles of pancreatic islet sections from people whose glucose tolerance was defined before pancreatic surgery during which a small portion of their pancreata became available for study.

Nutrient availability and the cell cycle are known to affect chromatin accessibility. A fundamental question is which mechanisms are involved in connecting nutrient levels, the cell cycle and chromatin regulation. In this issue, Zhang et al. reveal a signalling cascade whereby nutrient-sensing mTORC1 activates the cell-cycle regulator CDK2, thus leading to nuclear translocation of the metabolic enzyme triosephosphate isomerase 1 (TPI1). In the nucleus, TPI1 alters the levels of acetate and global histone acetylation through the metabolite dihydroxyacetone phosphate.

Neuropathy is a painful and potentially crippling disorder that is common in people with diabetes and often affects people with obesity, yet the underlying reason is poorly understood. Boyd al. now reveal that a diet enriched in ω-6 polyunsaturated fatty acids (PUFAs) triggers peripheral neuropathy in mice, and this effect is reversed by a diet enriched in ω-3 PUFAs. These findings may help explain the high incidence of neuropathies in people with diet-related obesity without diabetes, and may provide a potential target for the prevention and treatment of this metabolic and neurological disorder.

Preoperative exercise and a high fitness level can confer protection against postoperative stress. In this issue, Zhang et al. report that a short 4-week exercise regimen before liver surgery induces beneficial immunometabolic adaptations in Kupffer cells. Notably, the exercise-induced expression of immune-responsive gene 1 (Irg1) drives Kupffer cells toward an anti-inflammatory phenotype with decreased markers of postoperative hepatic ischaemia–reperfusion injury.

Malaria causes many changes in human metabolism, although the extent to which these changes underpin pathology and the host immune response remains poorly understood. In this issue of Nature Metabolism, Abdrabou et al. show that malaria is associated with elevated levels of circulating steroids in susceptible children and propose that these immunosuppressive lipids exacerbate disease.

Endothelial cell migration is indispensable for (tumour) angiogenesis and is fuelled by glycolysis. The metabolic underpinnings have been only partially unravelled to date, partly because of the lack of appropriate tools to analyse metabolic flux at the single-cell level. In this issue, Wu et al. introduce a novel imaging assay to capture glycolytic flux during motion in single endothelial cells. With this new tool, the authors uncovered a glycolysis-driven cytoskeletal remodelling apparatus that propels endothelial cell motility.

Reactive oxygen species (ROS) were long considered unwanted and dangerous by-products of mitochondrial metabolism, specifically oxidative phosphorylation. More recently, evidence has indicated that mitochondrial ROS are also essential signalling molecules that unexpectedly promote longevity, through a mechanism termed mitohormesis. In this issue, Timblin et al. expand this concept to immunity, specifically macrophage function, by demonstrating that mitochondrial ROS are required to prevent an excessive immune response.

Cancer is a complex disease without a specific single origin. Despite recent advances in this field, knowledge of the relationship between the metabolic networks of tumoural cells and the normal cells from their tissue of origin is limited. Here, Mahendralingam et al., by using a combination of multi-omic and cell-based techniques to characterize the metabolic programs of normal mammary epithelial cells, find that mammary cancer cells preserve the metabolic network and vulnerabilities of their cells of origin, thus uncovering a new putative Achilles’ heel in breast cancer.

Colchicine is an anti-inflammatory agent that suppresses myeloid cell activation and is commonly used to treat gout. In this issue of Nature Metabolism, Weng et al. demonstrate that colchicine exerts its anti-inflammatory effects in mice via the induction of the hormone GDF-15 in the liver.

Brown adipose tissue acquires increased thermogenic capacity with prolonged cold exposure through de novo recruitment of brown adipocytes. Studies by Shamsi et al. and Angueira et al. identify novel cellular origins of cold-induced brown adipocytes and further elucidate the molecular mechanism regulating the expansion of brown adipose tissue.

Redox cofactors are essential for the metabolic reactions that support cell proliferation. NADPH is important both to combat oxidative stress and to facilitate reductive reactions in biosynthesis. In this issue, Tran et al. find that the enzyme that produces mitochondrial NADPH is critical in enabling proline synthesis to support cell proliferation when environmental proline is limited.

Obesity is associated with mitochondrial dysfunction and chronic metabolic derailment. Cho et al. report that elevated adipose expression of the Hippo kinases STK3 and STK4 (STK3/4) in obesity and type 2 diabetes decreases the mass and oxidative capacity of adipocyte mitochondria. Genetic or pharmacological inhibition of STK3/4 restores mitochondrial mass and function in adipocytes and improves glucose homeostasis in mice with diet-induced obesity. These findings support STK3/4 as new targets for obesity-related diseases.

It is self-evident that consuming alcohol affects brain function and behaviour. What is not clear, however, is how alcohol does so. A new study shows that impairments in balance and motor coordination evoked by low-dose alcohol are mediated not by ethanol itself but by one of its metabolites, which is produced locally by astrocytes in the brain rather than in the liver.

Nutrient availability dictates cell differentiation and transition through the Dictyostelium discoideum life cycle. Kelly et al. reveal that the increase in reactive oxygen species associated with nutrient limitation coincides with a sequestration of available cysteine in glutathione, thus limiting sulfur-dependent mitochondrial respiration and promoting aggregation into the differentiated spore form.

Deciphering the origins of the various cells in atherosclerotic plaques, the regulation of their fates and their functions is an essential step towards developing strategies to limit or even reverse disease progression to myocardial infarction. In this issue, Newman et al. advance our understanding of the roles of non-vascular smooth muscle cells in the formation and maintenance of the fibrous cap, a structure in human atherosclerotic plaques that protects them against rupture—the proximal event typically underlying myocardial infarctions.

Exhaustion of pancreatic beta cells in the face of prolonged insulin resistance results in the development of type II diabetes. Ansarullah et al. now describe an inhibitor of beta-cell insulin signalling that, on removal, increases beta-cell mass and improves beta-cell function, with potential as a new way to address beta-cell failure.

Mitochondrial diseases are caused by genetic variants in either nuclear or mitochondrial DNA, and they have no known treatments. A new study by Perry et al. in this issue of Nature Metabolism used a drug screen to identify the widely available antibiotic doxycycline, an inhibitor of mitochondrial translation, as a potential pharmacological treatment for mitochondrial diseases.

A creatine futile cycle has been shown to contribute to energy expenditure in beige adipocytes in preclinical mouse models of obesity. In this issue of Nature Metabolism, Connell and colleagues show that creatine supplementation in healthy young female vegetarians unfortunately affects neither human brown adipocyte activity nor cold-induced energy expenditure.

Liver function depends on the temporal and zonal distribution of complementary metabolic tasks in hepatocytes. A new study by Droin et al. highlights how chronobiology and liver zonation orchestrate liver metabolism at single-cell resolution.